Intraocular irrigating solution having improved flow characteristics

ABSTRACT

Improved intraocular irrigating solutions are described. The solutions have enhanced viscosities that reduce the risk of damage to intraocular tissues during intraocular surgical procedures by reducing the turbulence of the solutions and dampening the movement of tissue fragments and air bubbles. The solutions preferably also have modified surface tensions that more closely resemble the surface tension of the aqueous humor.

BACKGROUND OF THE INVENTION

[0001] The present invention is directed to the field of intraocularsurgery. More specifically, the invention is directed to the irrigationof intraocular tissues during cataract surgery, vitrectomy surgery, andother intraocular surgical procedures. The invention providesintraocular irrigating solutions that have improved physical properties(e.g., flow characteristics) relative to prior ophthalmic irrigatingsolutions.

[0002] The field of intraocular surgery has advanced dramatically overthe past twenty years. The advancements in this art have resulted fromsignificant improvements in the areas of surgical techniques, surgicalequipment and associated pharmaceutical products. Despite theseadvancements, intraocular surgery is still a very delicate process withlittle room for error and great potential for harm to both oculartissues and, ultimately, the vision of the patient. Thus, there is anongoing need to improve ophthalmic surgical techniques and equipment, aswell as associated pharmaceutical products.

[0003] The present invention has resulted from an effort to improve thefluid dynamics of intraocular irrigating solutions, so as to providegreater protection for delicate intraocular tissues, while at the sametime enhancing the ability of ophthalmic surgeons to perform surgicalprocedures more efficiently.

[0004] Although various techniques have been used previously to removethe natural crystalline lens of the eye when it becomes afflicted with acataract, the majority of cataract surgeries today are performed byusing a procedure known as “phacoemulsification”. This procedureinvolves the use of a surgical handpiece having a tip that vibrates atan ultrasonic frequency. The vibrating tip of the handpiece is utilizedto disintegrate or “emulsify” the cataractous lens. This processnecessarily generates lens fragments or particles within the eye thatcan cause irreparable physical damage to corneal endothelial cells ifthose cells are left unprotected. The corneal endothelial cells arenormally protected during the phacoemulsification procedure by injectinga viscoelastic material (e.g., hyaluronic acid) into the eye to form aprotective barrier over the corneal endothelial cells. However, evenwith the presence of the viscoelastic material, lens particles continueto move in the eye, particularly when the viscoelastic material isremoved by a combined irrigating/aspiration handpiece following thephacoemulsification of the lens, prior to insertion of an artificiallens.

[0005] Due to continuous irrigation and aspiration, usually there is alot of turbulence in the anterior chamber, within which non-aspiratedlens fragments move around. In addition, the ultrasonic vibrationsproduced by the tip of the phacoemulsification handpiece push the lensfragments away from the tip thereby making it difficult to aspirate thefragments via the aspiration line in the tip of the handpiece. Themovement of these lens fragments can cause damage to the surroundingtissue.

[0006] In addition to the lens fragments, damage may result directlyfrom the turbulent flow of fluids intraocularly or from bubblesgenerated in the intraocular fluids by the phacoemulsificationhandpiece. Air bubbles generated during intraocular surgery have beenshown to result in severe injury to the corneal endothelium in as littleas twenty seconds. The turbulent flow of fluids may also cause tissuefragments to impact the delicate corneal endothelial cells or otherintraocular tissues, thereby causing mechanical trauma to such tissues.

[0007] For further background regarding these problems, please refer tothe following articles: Kim, et al., “Corneal endothelial damage by airbubbles during phacoemulsification”, Archives of Ophthalmology, volume115, pages 81-88, 1997; Beesley et al., “The effects of prolongedphacoemulsification time on the corneal endothelium”, Annals ofOphthalmology, volume 18, no. 6, pages 216-219, 1986; Kondoh et al.,“Quantitative measurement of the volume of air bubbles formed duringultrasonic vibration”, Folia Ophthalmogica Japan, volume 45, no. 7,pages 718-720, 1994 and Kim et al., Investigative Ophthalmology & VisualScience, volume 37, no. 3, S84, 1996.

[0008] The fluid dynamics of intraocular irrigating solutions is alsoimportant during vitrectomy procedures and various other types ofintraocular surgical procedures. Turbulence in intraocular fluids mayalso result from the movements of reciprocating vitrectomy handpieces,the alternating vacuum and irrigation modes of irrigation/aspirationhandpieces and movements of other surgical handpieces and devicesutilized in such procedures. The elimination or reduction of suchturbulence helps to protect the retina and other tissues located in theposterior segment of the eye, as well as tissues located in the anteriorsegment of the eye, such as the corneal endothelial cells.

[0009] In view of these potential complications, there is a need forintraocular irrigating solutions having improved physical propertiesthat: (1) reduce the potential for turbulence within the anterior andposterior chambers of the eye, (2) help to contain the movement oftissue fragments and air bubbles within the eye, and (3) facilitate theremoval of lens fragments and other tissue fragments by making it easierfor the surgeon to track the fragments with the tip of the surgicalhandpiece. The present invention is directed to fulfilling this need.Specifically, the present invention is directed to the provision of anirrigating solution that provides for greater control of the movement oftissue fragments, air bubbles and other particles duringphacoemulsification, vitrectomy and other intraocular surgicalprocedures. This control of particle movement is fundamentally differentfrom the above-discussed use of a layer of viscoelastic material toprotect the corneal endothelial cells by means of a cushioning effect.The irrigating solution of the present invention is designed to providea protective effect beyond that obtained by means of viscoelasticagents.

SUMMARY OF THE INVENTION

[0010] The present invention is directed to the provision of intraocularirrigating solutions that help to prevent the risk of damage tointraocular tissues, while facilitating the efficiency of the surgicalprocedures. The irrigating solutions of the present invention are lowviscosity solutions that exhibit less turbulence in the presence ofphacoemulsification handpieces and other intraocular surgical devices.These solutions also restrain the movement of air bubbles and tissuefragments within the eye, and generally dampen the impact of ultrasonichandpieces, liquefracture handpieces, irrigation/aspiration handpieces,microscissors, vitrectomy handpieces and other surgical devices onintraocular tissues. The restrained movement of lens fragments withinthe eye protects ophthahnic tissues, and facilitates a more efficientsurgical procedure by enabling the ophthalmic surgeon to locate andremove lens fragments more readily.

[0011] The intraocular irrigating solutions of the present inventionhave a viscosity greater than that of aqueous humor, but preferably havea surface tension similar to that of aqueous humor. Existing irrigatingsolutions generally have a viscosity similar to that of aqueous humor,but have surface tension higher than that of aqueous humor.

[0012] The present inventors have found that a slight enhancement of theviscosity of intraocular irrigating solutions greatly improves theability of the solutions to protect intraocular tissues by containingthe movement of tissue fragments and generally reducing the turbulenceof the intraocular fluids, thereby making it easier for the fragments tobe tracked and removed via aspiration. This slight enhancement ofirrigating solution viscosity is also beneficial in vitrectomyprocedures because it reduces the pulsatile movement of the retinaltissue and limits collateral tissue damage in the eye. The reduction ofpulsatile movement of retinal tissue is particularly important in caseswhere the retina is partially detached.

[0013] The overall performance of the irrigating solutions of thepresent invention can be further enhanced by including an agent whichreduces the surface tension to a level comparable to that of aqueoushumor, thereby making the solutions more physiological.

BRIEF DESCRIPTION OF DRAWINGS

[0014]FIG. 1 is a graph showing the effect of viscosity on flow rate;and FIG. 2 is a graph showing the relationship between HPMCconcentration and accumulation rate.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The irrigating solutions of the present invention comprise abalanced electrolyte solution and an amount of a biologically compatibleviscosity-adjusting agent sufficient to enhance the viscosity of theelectrolyte solution.

[0016] The electrolyte solution utilized in the present invention willtypically be a balanced salt solution, such as BSS™ (Balanced SaltSolution) Sterile Irrigating Solution manufactured by AlconLaboratories, Inc., or BSS PLUS™ (Balanced Salt Solution) SterileIrrigating Solution, also manufactured by Alcon Laboratories, Inc.However, the invention is not limited relative to the types of balancedsalt solutions or other electrolyte/nutrient solutions that may beutilized as a building block for the solutions of the present invention.

[0017] The agents utilized to adjust the viscosity of the electrolytesolution will comprise one or more compounds that are compatible withintraocular tissues, such as: chondroitin sulfate, sodium hyaluronate orother proteoglycans; cellulose derivatives, such as hydroxypropylmethylcellulose (“HPMC”), carboxy methylcellulose (“CMC”), andhydroxyethyl cellulose (“HEC”); collagen and modified collagens;galactomannans, such as guar gum, locust bean gum and tara gum, as wellas polysaccharides derived from the foregoing natural gums and similarnatural or synthetic gums containing mannose and/or galactose moietiesas the main structural components (e.g., hydroxypropyl guar); xanthangum; gellan gums; alginate; chitosans; polyvinyl alcohol; carboxyvinylpolymers (e.g., carbomers such as the Carbopol™ brand polymers availablefrom B. F. Goodrich); and various other viscous or viscoelastomericsubstances, including but not limited to those described in U.S. Pat.No. 5,409,904 (Hecht, et al.), the entire contents of which are herebyincorporated by reference in the present specification.

[0018] The following patent publications may be referred to for furtherdetails concerning the above-listed viscosity-enhancing agents: U.S.Pat. No. 4,861,760 (gellan gums); U.S. Pat. No. 4,255,415 and WIPOPublication No. WO 94/10976 (polyvinyl alcohol); U.S. Pat. No. 4,271,143(carboxyvinyl polymers); WIPO Publication No. WO 99/51273 (xanthan gum);and WIPO Publication No. WO 99/06023 (galactomannans). The entirecontents of the foregoing references pertaining to the structures,chemical properties and physical properties of the respective viscosityenhancing agents described above are hereby incorporated in the presentspecification by reference.

[0019] The above-described viscosity-adjusting agents will be utilizedin an amount sufficient to provide the irrigating solutions of thepresent invention with an enhanced viscosity. As utilized herein, thephrase “enhanced viscosity” means a viscosity which is greater than theviscosity of aqueous humor and prior irrigating solutions, both of whichgenerally have viscosities of approximately 1 centipoise (“cps”). Theirrigating solutions of the present invention will typically haveviscosities of from greater than 1 cps to about 15 cps, preferably fromabout 2 to about 7 cps.

[0020] The amount of viscosity adjusting agent utilized will varydepending on the degree of viscosity enhancement desired and thespecific agent or agents selected. However, the concentration of theviscosity-adjusting agent in the irrigating solutions of the presentinvention will typically range from about 0.1 to about 1.0 weight/volumepercent (“w/v %”) for polymers such as HPMC.

[0021] It should be noted that it is necessary to achieve a balancebetween: (a) enhancing the viscosity of the solution, and (b)maintaining a solution viscosity that is acceptable for use with theirrigation/aspiration system employed during intraocular surgicalprocedures. FIG. 1 of the accompanying drawings is a graph showing theflow rate of irrigating solutions of different viscosities through anormal irrigationi/aspiration tip in the Series 20000 Legacy™ (“STTL”)surgical operating system available from Alcon Laboratories, Inc. Duringgeneration of these data, all the settings on the STTL system weredefault instrumental settings. FIG. 1 clearly shows the effect ofincreasing viscosity on flow rate of the irrigating solution, which isusually flowing under gravity.

[0022] During a surgical procedure, aspiration is carried out byapplying vacuum through the tip of a surgical handpiece. Generally, themaximum vacuum or suction capability of the system is such that theirrigation rate is higher than the aspiration rate to maintain positiveflow. Hence, the increase in viscosity of the irrigation solution shouldbe such that the flow rate remains greater than the maximum aspirationrate. FIG. 2 of the accompanying drawings illustrates this point.

[0023] Increasing the concentration of the viscosity-adjusting agentincreases the viscosity of the solution, so at the same bottle height,the normal gravity fed irrigation flow rate of fluid into the eyedecreases. As the net irrigation rate decreases, the effectiveaspiration rate, which is controlled independently by a peristaltic pumpon the STTL, increases. Hence, the accumulation rate goes from apositive to a negative value. A minimum irrigation rate of 1milliliter/minute of aspiration is needed to prevent drying up of thetissue. These competing factors must be balanced. In the case of HPMC,it has been determined that a HPMC concentration of 0.27 w/v % providesthe desired level of viscosity enhancement without impeding normalirrigation and aspiration functions. It should be noted that this idealconcentration was determined using HPMC (E4M) in connection with theSTTL surgical operating system and a standard phacoemulsification tip.The ideal concentration may vary somewhat, depending on the surgicaloperating system and phacoemulsification tip utilized.

[0024] The preferred viscosity-adjusting agent ishydroxypropylmethylcellulose (“HPMC”). The present inventors have foundthat the addition of HPMC to a conventional balanced salt solutionresults in a significant reduction in turbulence during intraocularsurgery, relative to the turbulence seen with the balanced salt solutionalone. The preferred concentration of HPMC is about 0.2 to 0.3 w/v %,but this range may vary slightly depending on the particular ophthalmicsurgical system being utilized and the instrument settings of thatsystem. Irrigating solutions containing this concentration of HPMC willhave a viscosity of about 4 to 6 cps. The most preferredviscosity-adjusting agent is HPMC (E4M) at a concentration of 0.22 to0.27 w/v %.

[0025] As indicated above, the irrigating solutions of the presentinvention preferably also include an agent to modify the surface tensionof the solutions so as to resemble the surface tension of the aqueoushumor. The surface tension of the aqueous humor is approximately 50dynes per centimeter (“dynes/cm). The irrigating solutions of thepresent invention will therefore preferably have a surface tension inthe range of 40 to 60 dynes/cm or somewhat less.

[0026] It should be noted here that viscosity can be increased by anappropriate agent without affecting surface tension, and that surfacetension can be reduced to the level of aqueous/vitreous humor byinclusion of an appropriate surface-active agent independent ofviscosity. Thus, these two physical properties of irrigating solutionsare independent of each other. However, in some cases, theviscosity-adjusting agent may also function as the surface tensionreducing agent. This is true with respect to the preferred embodiment ofthe present invention, wherein HPMC is utilized both as aviscosity-adjusting agent and a surface tension reducing agent.

[0027] In other cases, it may be necessary to add a separate agent tothe irrigating solution for purposes of reducing the surface tension ofthe solution. Possible agents which can be utilized for this purposeinclude: Polyoxyl 35 castor oil (Cremophore™ EL and Cremophore™ EL-P,available from BASF Corp.), Polyoxyl 40 Hydrogenated Castor Oil(HCO-40), Solutol™ HS 15 (BASF Corp.), Polysorbate 80, Tocophersolan(TPGS), and other ophthahnically acceptable surface active agents.

[0028] The following examples are provided to further illustrate variousfeatures of the present invention.

EXAMPLE 1

[0029] Component Amount (w/v %) Function HPMC (E4M) 0.1 to 0.3 Viscosityand Surface Tension Modifier Sodium Chloride 0.744  Tonicity AgentPotassium Chloride 0.0395 Essential Ion Dibasic Sodium Phosphate 0.0433Buffering Agent (Anhydrous) Sodium Bicarbonate 0.219% + 20% xsPhysiological Buffer Hydrochloric Acid Adjust pH pH Adjust SodiumHydroxide Adjust pH pH Adjust Water for Injection 100% Vehicle

[0030] The above-described formulation may be prepared as follows:First, the water for Injection is brought close to boiling or atboiling. The HPMC is then slowly added to the water under continuousstirring to thoroughly disperse it in the water. Then the mixture isslowly allowed to cool, stirring continuously. Once at room temperature,the mixture should start clearing up. Then the mixture is storedovernight in an appropriate container to fully hydrate the HPMC. Thefollowing day, the remaining ingredients are added to the HPMC solution,additional water for injection is added if needed to bring the solutionto final volume, and the final solution is filtered, packaged in bottlesand autoclaved.

EXAMPLE 2

[0031] Component Amount (w/v %) Function HPMC (E4M) 0.1 to 0.3 Viscosityand Surface Tension Modifier Sodium Chloride 0.64  Tonicity AgentPotassium Chloride 0.075 Essential Ion Calcium Chloride (Dihydrate)0.048 Essential Ion Magnesium Chloride 0.03  Essential Ion (Hexahydrate)Sodium Acetate (Trihydrate) 0.039 Buffering Agent Sodium Citrate(Dihydrate) 0.17  Buffering Agent Hydrochloric Acid Adjust pH pH AdjustSodium Hydroxide Adjust pH pH Adjust Water for Injection 100% Vehicle

[0032] The above-described formulation may be prepared by means of themethod described in Example 1, above.

EXAMPLE 3

[0033] Three solutions were prepared and tested to evaluate the physicalproperties of the solutions of the present invention versus relatedsolutions. The solutions tested and the respective physical propertiesof the solutions were as follows: Osmolality Viscosity Surface TensionSolution mOsm/kg (cps) dynes/cm² BSS* 304, 305 1.02, 1.06 70, 73 BSS +0.05% 305, 305 0.99, 1.01 43, 43 cremophor BSS + 0.3% 320, 322 6.9, 7.048, 49 HPMC (grade E4M)

[0034] As indicated above, the addition of 0.3% HPMC to the BSS solutionincreased the viscosity from approximately 1 cps to 7 cps, and reducedthe surface tension from approximately 71.5 dynes/cm to approximately48.5 dynes/cm. Thus, the addition of this amount of HPMC increased theviscosity of the balanced salt solution and reduced its surface tension,in accordance with the basic principles of the present invention.Conversely, the addition of 0.05% cremophor to the balanced saltsolution had no effect on viscosity, but reduced the surface tension ofthe balanced salt solution from approximately 71.5 dynes/cm to 43dynes/cm.

[0035] The above-identified solutions were tested in a simulatedintraocular surgery model to determine if the addition of cremophor andHPMC to the balanced salt solution affected the performance of thesolution relative to the turbulence of the solution during intraocularsurgical procedures. It was determined that the addition of cremophor tothe balanced salt solution, although effective in reducing the surfacetension of the solution, had little if any effect on the performance ofthe balanced salt solution. However, the solution containing HPMCdemonstrated much less turbulence than the balanced salt solution alone.This turbulence was judged based on the movement of air bubbles and themovement of lens fragments.

[0036] The spinning and rotation of lens fragments seen with thebalanced salt solution alone was reduced significantly by the inclusionof HPMC in the solution. The dampening of the movement of the lensparticles facilitated an easier removal of the particles from the eyeduring the simulated surgical procedure. This dampening effectfacilitated a more efficient surgical procedure and reduced the timerequired for the procedure.

[0037] Conversely, there appeared to be no difference between thebalanced salt solution alone and the balanced salt solution containingcremophor with regard to bubble formulation, rate of flow or the visualhydrodynamics of the irrigating solutions.

[0038] The foregoing results confirm that the addition of a small amountof a viscosity enhancing agent reduces the turbulence of intraocularfluids during surgical procedures, dampens the movement of bubbles andlens fragments, and generally renders the procedure more efficient.

We claim:
 1. An improved intraocular irrigating solution comprising anamount of a viscosity-adjusting agent sufficient to provide the solutionwith an enhanced viscosity, and an oplithalmically acceptable vehicletherefor.
 2. An improved solution according to claim 1, wherein thesolution contains the viscosity-adjusting agent in an amount sufficientto provide the solution with a viscosity greater than 1 cps.
 3. Animproved irrigating solution according to claim 2, wherein the solutioncontains the viscosity-adjusting agent in an amount sufficient toprovide the solution with a viscosity of from greater than 1 cps to 50cps.
 4. An improved irrigating solution according to claim 3, whereinthe solution contains the viscosity-adjusting agent in an amountsufficient to provide the solution with a viscosity of from 2 to 7 cps.5. An improved irrigating solution according to claim 1, wherein theviscosity-adjusting agent is selected from the group consisting ofproteoglycans, cellulose derivatives, collagen or modified collagen,galactomannans, xanthan gums, gellan gums, alginate, chitosans,polyvinyl alcohol, and carboxyvinyl polymers.
 6. An improved irrigatingsolution according to claim 5, wherein the viscosity-adjusting agentcomprises hydroxypropyl methylcellulose.
 7. An improved irrigatingsolution according to claim 1, further comprising a surface tensionmodifying agent in an amount sufficient to provide the solution with asurface tension in the range of 40 to 60 dynes/cm.
 8. An improvedirrigating solution according to claim 1, wherein the enhanced viscosityof the solution reduces the turbulence of the solution during anintraocular surgical procedure.
 9. A method of reducing the turbulenceof intraocular fluids during an intraocular surgical procedure, whichcomprises irrigating intraocular tissue with the solution of claim 1.